B lymphocytes and the antibodies they produce play a critical role in host defense against microbes and in autoimmune diseases. A hallmark of adaptive immunity is heterogeneity of cell fate among antigen-experienced B cells. Substantial preliminary data suggest B cells can diversify the fates and functions of their daughter cells using an evolutionarily conserved strategy to allocate unequal amounts of key components. This project will test whether asymmetric cell division is a cardinal feature of the early B cell-mediated immune response. The aims will examine whether a deterministic mechanism is used to diversify the initial class switch choices of sibling B cells, and whether asymmetric division i used to meet the opposing demands of terminal differentiation and self-renewal. This project will also examine whether ancestral regulators of cell polarity are responsible for establishing cell biological features necessary for asymmetric division, and how asymmetrically inherited proteins could mediate fate disparity in daughter B cells. These studies should provide a framework for rational engineering of immune responses and vaccines against microbial agents and address fundamental uncertainties regarding the principle of clonal selection of lymphocytes in response to infectious diseases or during situations when our immune cells attack our own selves.